Transcript Organism Classification

Organism Classification
Hyphae
Aspergillus species, pseudallescheria boydii
Dermatophytes (Trichophyton species, Microsporum
species), Phialophora species, Fusarium species.
Dimorphic Fungi
Blastomyces, coccidioides, Histoplasma, Sporothrix.
Grow as a mold in nature (27c) but quickly convert to parasitic yeast form after infecting
the host (37c).
Yeast
Candida spesies, Cryptococcus neoformans
Clinical classification of
mycoses
Classification
Superficial
versicolor
Site Infected
Stratum corneum
Example
Tinea
& hair
Cutaneous
epidermis & nails
Dermatophytosis
Subcutaneous
Dermis &
Sporothrichosis
subcutaneous tissue
Systemic
Disease of 1
Candidiasis
internal organs
Cryptococcosis
Antifungics Drugs
Classification:
Antifongic Agents
Polyene
Flucytosine
Azoles
Nystatin
Amphotericin B
Imidazoles
Allylamines
Triazoles
Terbinafine
Ketoconazole
Fluconazole
Miconazole
Itraconazole
Clotrimazole
Ravuconazole
Econazole
Posaconazole
Isoconazole
Voriconazole
Griseofulvine
Naftifine
Pneumocandins
Caspofungin
Antifungal Agents
1- inhibitors of the fungal cell mb ( polyenes,
azoles, allylamines)
2- inhibitors of DNA (flucytosine)
3- inhibitors of cell wall biosynthesis
(caspofungin)
Adapted from Ghannoum MA and RiceLB Clin Micro Rev. 1999;12:501-517.
Mechanism of action of azoles
Azoles antifungals exert their effects primarily by
inhibiting the fungal cytochrome P450 3A enzyme
lanosterol 14-α-demethylase, preventing the
conversion of lanosterol to ergosterol.
This in turn leads to depletion of ergosterol (a
regulator of fungal cell membrane fluidity and
asymmetry) and accumulation of sterol precursors.
As a result of ergosterol depletion, the integrity
and function of the fungal cell membrane is
disrupted, eventually leading to cell lysis
Mechanism of action of
Amphotericin
Amp B acts principally by binding to
ergosterol in the fungal cell menbrane,
effectively creating pores in the cell mb,
leading to depolarisation of the mb and
cell leakage.
Amp B binds>>> to ergosterol than to
cholesterol
Toxic effects
Mechanism of action of 5Flucytosine
= fluorinated cytosine analogue
Acts by inhibiting nucleic acid synthesis
It is actively transported into cells, where it is
metabolically transformed by deamination to
toxic metabolite 5-Fu. 5Fu convert to 5-fluoridine
triP=> antimetabolite => disrupts Prot synthesis.
monoP => -- thymidylate synthase=>disrupts
DNA synthesis.
Resistance in monotherapie+++
Diffuse LCR 60-80%
Mechanism of action of
allylamines
Inhibition of sterol biosynthesis by interfering
with squalene epoxidase (critical enzymes
in the biosynthesis of ergosterol).
faulty cell mb with altered permeability
Mechanism of action of
Griseofulvin
Inhibits growth by inhibiting fungal cell
mitosis caused by polymerization of cell
microtubules
 It has activity only against dermatophyte
fungi

Mechanism of action of
caspofungin

Interfering with 1,3 ß glucan, preventing
synthesis of essential cell wall
polysaccharides
protect the cell from osmotic and structural
stresses
 Cilofungin 1= but was dropped bcs of the
toxicity of Hydrophobic vehicle.

1- Clotrimazole 1= imidazoles
inadequate for the ttt of systemic infection,
bcs it induce its own metabolism rapidly (oral,
or IV)
 It use now largely as topical therapy
(vulvovaginal candidiasis). [Canestan]
2- Miconazole poorly soluble in water, therefore
administer in castor oil vehicle for IV admi.
 This vehicle is responsible for many adverse
effects: Phlebitis, pruritis, N, V, anemia,
thrombocytosis and hyperlipidemia (high
dose), cardiorespiratory arrest (rapid infusion).
 Ttt of inf. Caused by pseudallescheria boydii
 Topical use (vulvovaginal candediasis, and
superficial skin inf).
3- Ketoconazole is poorly soluble in
aqueous fluids (acidic PH<3).
Absorption is impaired in pt w elevated
gastric PH
SE: GI discomfort >50%
inhibition of adrenal steroid synthesis
(gynecomastia, libido,
azoospermia, secondary to
testosterone synthesis following high
daily dosage >600mgd or during
prolonged admi of lower dosages.
4- Itraconazole (vehicle= cyclodextrin)
have greater specifity against fungal
versus mammalian cyt P450.
same SE of Ketoconazole.
vehicle is not absorbed following oral
adm,
Use of IV formulation is limited to 2w,
bcs of potential nephrotoxicity
secondary to accumulation of vehicle.
5- Fluconazole is markedly
differentpharmacologic featurs:
small molecular weight Complete
absorption of
low protein binding
drug
water solubility
Well tolerated, does not inhibit testicular
or adrenal steroidogenesis, reversible
alopecia occurs after several months of
ttt with high doses.
6- Voriconazole, Ravuconazole,
Posaconazole
New Triazoles have activity against
aspergillose and Fluconazole- resistant
strains of candida Krusei, albicans,
glabrata.
Posaconazole is the only drugs that acts
against zygomycetes.
It has a long side chains that appear to
stabilize binding to mutated cyp51a1.
7- Amp B: dose and duration should be
individulized.
Pt stable, no evidence of deep-seated inf
=>0.3mg/Kg/d at least 14d
Pt unstable, have deep..( organ involvement)
=>0.5-0.6mg/Kg/d for at least 14d
Pt developp septic shock =>1mg/Kg/d
Max doses 2-4g
Lean body mass
Initial T1/2=24-48h; terminal T1/2= 15days =>
practice of every other day, (0.5mg/kg/d or
1mg/kg qod)
Based on the potential for reduce nephrotoxicity
Faster infusion rates (< 4-6h) r associated w :
*Earlier onset of infusion-related reaction (
fever, chills, headache, vomiting..)
*Cardiac arrythmias (high serum [Amp] can
precipitate severe cardiac adverse events
most often in pt who r anuric or have previous
cardiac disease, therefore we should do
ECG.)
The dose- related side effects is renal damage,
that manifests by:
-azotemia
-HypoK+
-HypoMgnesimia
Amp B related renal toxicity is reversible within
2w after therapy has been discontinued.
Adm of NS 250ml bfr AmpB can reduce
nephrotoxicity
Should not mix w NS bcs Na causes Ampb to
precipitate into Iv admixture.
Anemia is associated w decrease renal
production of erythropoietine; it is resolve
after discontinuation of AmpB; it need not to
be treated.
No need dose adjustment w chronic reanl or
hepatic failure (5-10% is eliminated in urine
and bile, it is cleared by reticuloendothelial
system).
8- Cancidas is metabolised and excreted
35% in feces, and 41% in urine.
No adjustment is necessary for pt w renal
insufficiency.
Monitor liver fct test( surtout if used w
cyclosporin where it increased by 2-3
fold)
May cause histamine release (rash, facial
swelling)
Slow infusion 1h
Lipid form of Amp B: is indicated for
treatment of invasive fungal infections in pt
who r refractory to or intolerant of
conventional amp B.
They r less toxic, more potent.
Abelcet, Ambisome
Antifungal CNS penetration
IV amp B have a limited penetration into CSF bcs
of high bound to lipid([
ampB] 2-4% of the
serum conc)
 Intraventricular or intrathecal adm (0.25-0.5mg
diluted w 5ml glucose5%
Flucytosine might be alternative to ampB (74% of
serum conc)
Fluconazole (60% of serum conc) at dose
400mg/d
Relapse is high when fluc. is stopped
In pregnancy
Azoles are teratogenic (factor c)
Griseofulvin and flucytosin are teratogenic
(factorc)
Amp B ( factor b) has been the mainly drug
used in pregnancy for the treatment of
systemic mycoses.
Terbinafine (factor b), ( ther have been no
reports of the use of terbinafine in
pregnancy.